PURPOSE: Management of metastatic renal cell cancer (mRCC) has undergone a paradigm shift with immune-checkpoint inhibitors (ICI) in the first-line setting. However, direct comparative data are inadequate to inform treatment decisions. Therefore, we aimed to assess first-line therapy for mRCC and indirectly compare the efficacy and safety of currently available treatments. MATERIALS AND METHODS: Multiple databases were searched for articles published before June 2020. Studies that compared overall and/or progression-free survival (OS/PFS) and/or adverse events (AEs) in mRCC patients were considered eligible. RESULTS: Six studies matched our eligibility criteria. For OS, pembrolizumab plus axitinib [hazard ratio (HR) 0.85, 95% credible interval (CrI) 0.73-0.98] and nivolumab plus ipilimumab (HR 0.86, 95% CrI 0.75-0.99) were significantly more effective than sunitinib, and pembrolizumab plus axitinib was probably the best option based on analysis of the treatment ranking. For PFS, pembrolizumab plus axitinib (HR 0.86, 95% CrI 0.76-0.97) and avelumab plus axitinib (HR 0.85, 95% CrI 0.74-0.98) were statistically superior to sunitinib, and avelumab plus axitinib was likely to be the preferred option based on analysis of the treatment ranking, closely followed by pembrolizumab plus axitinib. Nivolumab plus ipilimumab had significantly lower rates of serious AEs than sunitinib. CONCLUSION: Pembrolizumab plus axitinib seemed to be the most efficacious first-line agents, while nivolumab plus ipilimumab had the most favorable efficacy-tolerability equilibrium. These findings may facilitate individualized treatment strategies and inform future direct comparative trials in an expanding treatment options without direct comparison between approved drugs.

Cancer Prognostics and Health Outcomes Unit University of Montreal Health Centre Montreal Canada

Clinical Division of Oncology Department of Medicine 1 and Comprehensive Cancer Center Medical University of Vienna Vienna Austria

Department of Urology 2nd Faculty of Medicine Charles University Prague Czech Republic

Department of Urology Ehime University Graduate School of Medicine Ehime Japan

Department of Urology European Institute of Oncology IRCCS Milan Italy

Department of Urology Medical University of Vienna Währinger Gürtel 18 20 1090 Vienna Austria

Department of Urology The Jikei University School of Medicine Tokyo Japan

Department of Urology University Hospital of Tours Tours France

Department of Urology University of Texas Southwestern Dallas TX USA

Department of Urology Weill Cornell Medical College New York NY USA

Division of Urology Department of Special Surgery The University of Jordan Amman Jordan

European Association of Urology Research Foundation Arnhem Netherlands

Institute for Urology and Reproductive Health 1 M Sechenov 1st Moscow State Medical University Moscow Russia

Karl Landsteiner Institute of Urology and Andrology Vienna Austria

Research Center for Evidence Based Medicine Tabriz University of Medical Sciences Tabriz Iran

Université François Rabelais de Tours PRES Centre Val de Loire Tours France

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